Indole compounds and pharmaceutical use thereof

Production of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole

##STR00040##

Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g, 697 mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of 3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 ml) under ice-cooling over about 1 hr, and the mixture was stirred for 1 hr. Then, a solution of ethyl formate (99 g, 1.3 mol) in tetrahydrofuran (250 ml) was added dropwise over about 1 hr, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated and extracted with 2 N aqueous sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of the obtained 4,4-dimethyl-2-oxocyclohexanecarbaldehyde in methanol (376 ml) was added dropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) in methanol (31 ml) with heating under reflux over about 1 hr, and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole. To a solution of the obtained 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole in N,N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) and potassium hydroxide (121 g, 1.8 mol) at room temperature, and the mixture was stirred for about 4 hr. Then, under ice-cooling, an aqueous solution (800 ml) of sodium hydrogensulfite (80 g) was added dropwise. Water (2 L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, hexane (350 ml) was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, yield 23%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.94 (s, 6H), 1.47 (t, 2H, J=6.38 Hz), 2.21 (t, 2H, J=6.38 Hz), 2.33 (s, 2H), 12.69 (s, 1H).

Production of tert-butyl 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate

##STR00041##

To a solution of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, 147 mmol), triethylamine (22 ml, 155 mmol) and 4-dimethylaminopyridine (824 mg, 7 mmol) in tetrahydrofuran (163 ml) was added dropwise a solution of di-tert-butyl dicarbonate (34 g, 155 mmol) in tetrahydrofuran (41 ml) at room temperature over 40 min, and the mixture was stirred for 30 min. Then, the reaction mixture was is concentrated under reduced pressure. The residue was slurry-washed in hexane (130 ml) at 60° C. and ice-cooled. The crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (53 g, yield 95%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.95 (s, 6H), 1.46 (t, 2H, J=6.38 Hz), 1.56 (s, 9H), 2.23 (t, 2H, J=6.26 Hz), 2.63 (s, 2H).

Reference Example 2

Production of 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate

Production of methyl 1H-indole-6-carboxylate

##STR00042##

Under a nitrogen atmosphere, to a solution of 1H-indole-6-carboxylic acid (121 g, 752 mmol) in N,N-dimethylformamide (360 ml) was added potassium carbonate (124 g, 900 mmol), and the mixture was stirred at room temperature for 1 hr. Then, iodomethane (56 ml, 900 mmol) was added dropwise at room temperature over 15 min, and the mixture was stirred for 2 hr. Then, to the reaction solution were added water (1.2 L) and hexane (100 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed successively with water and hexane, and dried under reduced pressure to give the title compound (115 g, yield 87%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.85 (3H, s), 6.53 (1H, d, J=1.61 Hz), 7.60-7.63 (3H, m), 8.07 (1H, s), 11.48 (1H, s).

Production of 1-tert-butyl 6-methyl indole-1,6-dicarboxylate

##STR00043##

To a solution of methyl 1H-indole-6-carboxylate (124 g, 708 mmol) in tetrahydrofuran (500 ml) was added 4-dimethylaminopyridine (865 mg, 7 mmol). Then, a solution of di-tert-butyl dicarbonate (156 g, 715 mmol) in tetrahydrofuran (150 ml) was added dropwise at room temperature over about 1 hr, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound (193 g, yield 99%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.65 (9H, s), 3.89 (3H, s), 6.82H, dd, J=3.63, 0.86 Hz), 7.74 (1H, d, J=8.06 Hz), 7.85 (1H, dd, J=8.06, 0.86 Hz), 7.87 (1H, d, J=3.63 Hz), 8.76 (1H, d, J=0.81 Hz).

Production of 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate

##STR00044##

To a solution of 1-tert-butyl 6-methyl indole-1,6-dicarboxylate (107 g, 389 mmol) in tetrahydrofuran (135 ml) was added triisopropyl borate (135 ml, 584 mmol), and the inside temperature was cooled to −5° C. Then, a solution (253 ml, 506 mmol) of lithium diisopropylamide in hexane was added dropwise over 1.5 hr while maintaining the inside temperature at −5° C. or below, and the mixture was further stirred for 1 hr. Then, to the reaction solution was added dropwise 10% aqueous citric acid solution (1.2 L) under ice-cooling. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was slurry-washed with a mixed solvent of ethyl acetate (333 ml) and hexane (666 ml), and the precipitate was collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (73 g, yield 59%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.62 (s, 9H), 3.88 (s, 3H), 6.72 (d, 1H, J=0.88 Hz), 7.68 (t, 1H, J=4.08 Hz), 7.82 (dd, 1H, J=8.16, 1.54 Hz), 8.33 (s, 2H), 8.78 (t, 1H, J=0.77 Hz).

Reference Example 3

Production of (S)-2-(morpholin-4-yl)propionic acid

Production of benzyl (S)-2-(morpholin-4-yl)propionate

##STR00045##

Under an argon atmosphere, to a solution of L-alanine benzyl ester tosylate (3.4 g, 9.7 mmol) and triethylamine (6.8 ml) in dimethyl sulfoxide (17 ml) was added a solution of 1-bromo-2-(2-bromoethoxy)ethane (1.5 ml, 12 mmol) in dimethyl sulfoxide (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. To the reaction solution were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (1.6 g, yield 64%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.20 (d, 3H, J=7.25 Hz), 2.44-2.59 (m, 4H), 3.35 (q, 1H, J=7.25 Hz), 3.47-3.59 (m, 4H), 5.16-5.09 (m, 2H), 7.29-7.40 (m, 5H).

Production of (S)-2-(morpholin-4-yl)propionic acid

##STR00046##

Under an argon atmosphere, to a solution of benzyl (S)-2-(morpholin-4-yl)propionate (43 g, 172 mmol) in methanol (430 ml) was added 20% palladium hydroxide-carbon (4.3 g) at room temperature, and the mixture was stirred for 3 hr under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (25.4 g, 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.17 (d, 3H, J=6.98 Hz), 2.47-2.63 (m, 4H), 3.17 (q, 1H, J=6.98 Hz), 3.50-3.63 (m, 4H).

Reference Example 4

Production of (3-oxomorpholin-4-yl)acetic acid

Production of 2-chloro-N-(2-hydroxyethyl)acetamide

##STR00047##

Under an argon atmosphere, to a solution of 2-aminoethanol (5 g, 82 mmol) and triethylamine (11.4 ml, 82 mmol) in tetrahydrofuran (60 ml) was added dropwise chloroacetyl chloride (6.2 ml, 78 mmol) under ice-cooling over 30 min, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (3.2 g, yield 30%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.16 (q, 2H, J=5.87 Hz), 3.42 (q, 2H, J=5.87 Hz), 4.06 (s, 2H), 4.71 (t, 1H, J=5.45 Hz), 8.18 (s, 1H).

Production of morpholin-3-one

##STR00048##

Under an argon atmosphere, to a solution of 2-chloro-N-(2-hydroxyethyl)acetamide (3.2 g, 23 mmol) in tetrahydrofuran (64 ml) was added sodium hydride (1.2 g, 30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, the mixture was stirred at room temperature for 1 hr, and further at 60° C. for 4 hr. After cooling, water (540 μl) was added, and the reaction mixture was dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (232 mg, yield 10%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.20-3.23 (m, 2H), 3.70-3.73 (m, 2H), 3.96 (s, 2H), 7.88-8.07 (brs, 1H).

Production of benzyl (3-oxomorpholin-4-yl)acetate

##STR00049##

Under an argon atmosphere, to a solution of morpholin-3-one (220 mg, 2.2 mmol) in N,N-dimethylformamide (2.2 ml) was added sodium hydride (105 mg, 2.6 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, benzyl bromoacetate (379 μl, 2.4 mmol) was added, and the mixture was stirred for 2 hr. To the reaction solution were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (321 mg, yield 59%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.40-3.43 (m, 2H), 3.83-3.85 (m, 2H), 4.08 (s, 2H), 4.21 (s, 2H), 5.16 (s, 2H), 7.32-7.41 (m, 5H).

Production of (3-oxomorpholin-4-yl)acetic acid

##STR00050##

Under an argon atmosphere, to a solution of benzyl (3-oxomorpholin-4-yl)acetate (319 mg, 1.3 mmol) in methanol (5 ml) was added 20% palladium hydroxide-carbon (64 mg) at room temperature. Then, the mixture was stirred for 2 hr under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (206 mg, yield over weight).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.37-3.40 (m, 2H), 3.82-3.84 (m, 2H), 4.03 (s, 2H), 4.06 (s, 2H), 12.22-13.57 (brs, 1H).

Reference Example 5

Production of tert-butyl 6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate

Production of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one

##STR00051##

Under a nitrogen atmosphere, to a solution of lithium bis(trimethylsilyl)amide (1M, 100 ml, 100 mmol) in tetrahydrofuran (200 ml) was added dropwise a solution of 1,4-dioxaspiro[4.5]decan-8-one (15.6 g, 100 mmol) in tetrahydrofuran (50 ml) at −78° C. over about 30 min, and the mixture was stirred for 30 min. Then, methyl iodide (2.5 ml, 120 mmol) was added dropwise over 5 min, and the mixture was stirred at −78° C. for 30 min, and at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted three times with diethyl ether. The combined organic layers were dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (10.6 g, yield 62%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.90 (3H, d, J=6.62 Hz), 1.65 (1H, t, J=13.01 Hz), 1.84-2.04 (3H, m), 2.19 (1H, ddd, J=14.50, 5.13, 3.03 Hz), 2.49-2.69 (2H, m), 3.85-4.06 (4H, m).

Production of 7-hydroxymethyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-one

##STR00052##

7-Methyl-1,4-dioxaspiro[4.5]decan-8-one (10.5 g, 62 mmol) was dissolved in methanolic potassium hydroxide solution (10 w/w %, 60 g). To the solution was added dropwise a solution of aqueous formaldehyde solution (37%, 4.6 ml) in methanol (5 ml) under ice-cooling over 20 min, and the mixture was stirred for 30 min. Then, to the reaction mixture were added 1 N hydrochloric acid and saturated aqueous ammonium chloride solution, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (6.9 g, yield 56%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.98 (3H, s), 1.67 (1H, dd, J=14.00, 1.41 Hz), 1.86-1.97 (2H, m), 2.08 (1H, dd, J=14.00, 1.61 Hz), 2.33-2.48 (2H, m), 3.42-3.50 (2H, m), 3.90-3.95 (4H, m), 4.63 (1H, t, J=5.24 Hz).

Production of (7-methyl-1,4-dioxaspiro[4.5]deca-7-yl)methanol

##STR00053##

To a solution of 7-hydroxymethyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-one (6.9 g, 65 mmol) in methanol (40 ml) was added p-toluenesulfonylhydrazide (7.4 g, 40 mmol), and the mixture was heated under reflux for 3 hr. Then, to the reaction solution were added methanol (120 ml), sodium cyanoborohydride (2.9 g, 46 mmol) and a solution (100 ml) of zinc chloride (3.1 g, 23 mmol) in methanol, and the mixture was heated under reflux for 2 hr. After cooling, 1 N aqueous sodium hydroxide solution (700 ml) was added, the mixture was filtered through celite, and the filtrate was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (4.0 g, yield 61%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.96 (3H, s), 1.18-1.87 (8H, m), 3.18 (1H, d, J=8.06 Hz), 3.35 (1H, dd, J=10.88, 6.45 Hz), 3.51 (1H, dd, J=10.88, 9.07 Hz), 3.93-3.94 (4H, m).

Production of 7-benzyloxymethyl-7-methyl-1,4-dioxaspiro[4.5]decane

##STR00054##

Under a nitrogen atmosphere, to a solution of (7-methyl-1,4-dioxaspiro[4.5]deca-7-yl)methanol (4.0 g, 21 mmol) in N,N-dimethylformamide (40 ml) was added sodium hydride (1.1 g, 27 mmol) under ice-cooling, and the mixture was stirred for 30 min. Then, to the reaction mixture was added benzyl bromide (3.1 ml, 25 mmol) at room temperature, and the mixture was further stirred for 1 hr. To the reaction mixture were added diethyl ether and water, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (5.7 g, yield 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.95 (3H, s), 1.14-1.19 (1H, m), 1.32-1.59 (7H, m), 3.20 (2H, dd, J=28.41, 8.66 Hz), 3.77-3.85 (4H, m), 4.45 (2H, s), 7.29-7.33 (5H, m).

(Step 5)

Production of 3-benzyloxymethyl-3-methylcyclohexanone

##STR00055##

To a solution of 7-benzyloxymethyl-7-methyl-1,4-dioxaspiro[4.5]decane (5.3 g, 19 mmol) in a mixed solvent of acetone (42 ml) and water (11 ml) was added pyridinium p-toluenesulfonate (4.8 g, 19 mmol), and the mixture was stirred with heating at 80° C. for 2 hr. After cooling, to the reaction mixture were added ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (3.9 g, yield 88%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.88 (3H, s), 1.43-1.49 (1H, m), 1.72-1.84 (3H, m), 2.01 (1H, dt, J=13.67, 1.43 Hz), 2.17-2.26 (2H, m), 2.32 (1H, d, J=13.45 Hz), 3.17 (2H, dd, J=10.81, 8.82 Hz), 4.47 (2H, s), 7.26-7.38 (5H, m).

(Step 6)

Production of tert-butyl 6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate

##STR00056##

In the same manner as in Reference Example 1, the title compound (3.8 g) was obtained from 3-benzyloxymethyl-3-methylcyclohexanone (3.9 g).

Reference Example 6

Production of (2-oxopiperidin-1-yl)acetic acid

Production of benzyl (2-oxopiperidin-1-yl)acetate

##STR00057##

Under a nitrogen atmosphere, to a solution of piperidin-2-one (9.8 g, 99 mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (4.4 g, 110 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, benzyl bromoacetate (19 ml, 120 mmol) was added, and the mixture was further stirred for 2 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (6.0 g, yield 24%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.62-1.66 (4H, m), 2.11 (2H, t, J=6.45 Hz), 3.10-3.12 (2H, m), 4.21 (2H, s), 5.18 (2H, s), 7.21-7.40 (5H, m).

Production of (2-oxopiperidin-1-yl)acetic acid

##STR00058##

Under a nitrogen atmosphere, to a solution of benzyl (2-oxopiperidin-1-yl)acetate (6.0 g, 24 mmol) in methanol (60 ml) was added 20% palladium hydroxide-carbon (400 mg) at room temperature, and the mixture was stirred for 4 hr under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (4.0 g, yield over weight).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.71-1.74 (4H, m), 2.23 (2H, t, J=6.04 Hz), 3.17-3.31 (2H, m), 3.94 (2H, s), 12.58 (1H, s).

Example 1

Production of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylacetamide

Production of 1-tert-butyl 6-methyl 2-(1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-1,6-dicarboxylate

##STR00059##

Under an argon atmosphere, to a solution of tert-butyl 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate obtained in Reference Example 1 (49 g, 130 mmol), potassium phosphate (110 g, 520 mmol) and (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex (11 g, 13 mmol) in a mixed solvent of 1,4-dioxane (780 ml) and water (330 ml) was added 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate (42 g, 130 mmol) obtained in Reference Example 2 in portions of 2 g with heating at 110° C. over 15 min, and the mixture was stirred for 5 min. After cooling, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (40 g, yield 58%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.01 (s, 6H), 1.40 (s, 9H), 1.48 (t, 2H, J=6.15 Hz), 1.57 (s, 9H), 2.41 (t, 2H, J=5.80 Hz), 2.72 (s, 2H), 3.90 (s, 3H), 7.06 (s, 1H), 7.77 (d, 1H, J=8.35 Hz), 7.89 (dd, 1H, J=8.35, 1.16 Hz), 8.73 (t, 1H, J=0.70 Hz).

Production of methyl 2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-6-carboxylate

##STR00060##

To a solution of 1-tert-butyl 6-methyl 2-(1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-1,6-dicarboxylate (39 g, 75 mmol) in a mixed solvent of methanol (180 ml) and tetrahydrofuran (120 ml) was added dropwise 2 N aqueous sodium hydroxide solution (149 ml, 298 mmol) under ice-cooling over 15 min, and the mixture was stirred for 15 min. Then, 1 N hydrochloric acid was added dropwise to adjust the pH to 5. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (23 g, yield 97%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J=6.38 Hz), 2.42 (s, 2H), 2.68 (t, 2H, J=6.15 Hz), 3.85 (s, 3H), 6.67 (s, 1H), 7.59 (s, 2H), 8.07 (s, 1H), 11.71 (s, 1H), 12.66 (s, 1H).

Production of methyl 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylate

##STR00061##

Under an argon atmosphere, to a solution of methyl 2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-6-carboxylate (23 g, 71 mmol) in N,N-dimethylformamide (230 ml) was added sodium hydride (6.3 g, 157 mmol) in portions of about 500 mg at an inside temperature of −10° C., and the mixture was stirred for 30 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (26 g, 157 mmol) was added dropwise over 15 min, and the mixture was further stirred for 2 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (33 g, yield 80%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.21 (s, 9H), −0.03 (s, 9H), 0.68 (t, 2H, J=8.00 Hz), 0.87 (t, 2H, J=8.12 Hz), 1.03 (s, 6H), 1.54 (t, 2H, J=6.26 Hz), 2.50 (s, 2H), 2.63 (t, 2H, J=6.26 Hz), 3.30-3.31 (m, 2H), 3.59 (t, 2H, J=8.00 Hz), 3.87 (s, 3H), 5.42 (s, 2H), 6.14 (s, 2H), 6.83 (d, 1H, J=0.70 Hz), 7.67-7.72 (m, 2H), 8.22 (s, 1H).

Production of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid

##STR00062##

To a solution of methyl 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylate (33 g, 57 mmol) in a mixed solvent of tetrahydrofuran (165 ml) and methanol (165 ml) was added 4 N aqueous sodium hydroxide solution (71 ml, 284 mmol), and the mixture was heated at 60° C. for 2 hr. After cooling, the reaction mixture was concentrated, 10% aqueous citric acid solution was added to the residue to adjust the pH to 5, and the mixture was extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (31 g, yield 97%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.21-−0.20 (m, 9H), −0.05-−0.03 (m, 9H), 0.68-0.71 (m, 2H), 0.85-0.91 (m, 2H), 1.03 (s, 6H), 1.54 (t, 2H, J=6.06 Hz), 2.63 (t, 2H, J=5.95 Hz), 3.57-3.61 (m, 2H), 5.42 (s, 2H), 6.13 (d, 2H, J=3.53 Hz), 6.82 (t, 1H, J=3.42 Hz), 7.65-7.70 (m, 2H), 8.20 (s, 1H).

(Step 5)

Production of benzyl (2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate

##STR00063##

Under an argon atmosphere, to a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid (26 g, 45 mmol), triethylamine (8.2 ml, 59 mmol) and benzyl alcohol (18 ml, 180 mmol) in toluene (260 ml) was added dropwise diphenylphosphoryl azide (12 ml, 54 mmol) at 115° C. over 2 hr. After cooling, water was added to the reaction mixture, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, and slurry-washed in hexane (210 ml) with heating at 60° C. The resulting crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (28 g, yield 91%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.19 (s, 9H), −0.03 (s, 9H), 0.69 (t, 2H, J=8.16 Hz), 0.86 (t, 2H, J=8.05 Hz), 1.02 (s, 6H), 1.52 (t, 2H, J=6.18 Hz), 2.59 (t, 2H, J=6.06 Hz), 3.58 (t, 2H, J=8.05 Hz), 5.17 (s, 2H), 5.38 (s, 2H), 5.96 (s, 2H), 6.61 (s, 1H), 7.10 (dd, 1H, J=8.49, 1.65 Hz), 7.34-7.46 (m, 6H), 7.86 (s, 1H), 9.71 (s, 1H).

(Step 6)

Production of benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate

##STR00064##

Under an argon atmosphere, to a solution of benzyl (2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate (3 g, 4.6 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (219 mg, 5.5 mmol) under ice-cooling, and the mixture was stirred for 10 min. Then, to the reaction mixture was added methyl iodide (0.6 ml, 6.9 mmol), and the mixture was further stirred for 3 hr. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.2 g, yield 69%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.21 (s, 9H), −0.03 (s, 9H), 0.66 (t, 2H, J=8.01 Hz), 0.86 (t, 2H, J=8.01 Hz), 1.02 (s, 6H), 1.53 (t, 2H, J=6.01 Hz), 2.49 (s, 2H), 2.60 (t, 2H, J=6.01 Hz), 3.29 (s, 3H), 3.29 (t, 2H, J=8.01), 3.59 (t, 2H, J=8.01 Hz), 5.09 (s, 2H), 5.39 (s, 2H), 6.00 (s, 2H), 6.70 (s, 1H), 7.03 (dd, 1H, J=8.41, 2.00 Hz), 7.26-7.37 (m, 5H), 7.44-7.59 (m, 2H).

(Step 7)

Production of N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine

##STR00065##

A solution of benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate (2.2 g, 3.1 mmol), 10% palladium-carbon (216 mg) and ammonium formate (989 mg, 16 mmol) in ethanol (30 ml) was heated under reflux for 2.5 hr. After cooling, the reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (1.4 g, yield 79%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.18 (s, 9H), −0.03 (s, 9H), 0.69 (t, 2H, J=8.41 Hz), 0.86 (t, 2H, J=8.41 Hz), 1.01 (s, 6H), 1.52 (t, 2H, J=6.41 Hz), 2.47 (s, 2H), 2.57 (t, 2H, J=6.41 Hz), 2.73 (d, 3H, J=5.21 Hz), 3.31 (t, 2H, J=8.41), 3.58 (t, 2H, J=8.41 Hz), 5.36 (s, 2H), 5.50 (q, 1H, J=5.21 Hz), 5.94 (s, 2H), 6.42-6.55 (m, 3H), 7.25 (d, 1H, J=8.41 Hz).

(Step 8)

Production of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylacetamide

##STR00066##

Under an argon atmosphere, to a solution of N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (100 mg, 0.18 mmol) and triethylamine (75 μl, 0.54 mmol) in chloroform (1.5 ml) was added acetyl chloride (19 μl, 0.27 mmol) at room temperature, and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide. A solution of the obtained N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide in N,N-dimethylformamide (1.4 ml) was added to tetrabutylammonium fluoride (1.8 ml, 1.8 mmol) concentrated in advance under reduced pressure. Ethylenediamine (0.7 ml) was added, and the mixture was stirred with heating at 90° C. for 24 hr. After cooling, water and ethyl acetate were added, and the organic layer was separated. Then, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (26 mg, yield 42%).

Example 2

Production of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-ethylacetamide

Production of N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylamine

##STR00067##

Under a nitrogen atmosphere, benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylcarbamate was obtained in the same manner as in Example 1, Step 6, from benzyl (2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate obtained in Example 1, Step 5. To a solution of the obtained benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylcarbamate (979 mg, 1.4 mmol) in methanol (8 ml) was added 20% palladium hydroxide-carbon (400 mg). Then, the mixture was stirred under a hydrogen atmosphere at normal pressure for 1.5 hr. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (802 mg, yield 100%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.18 (s, 9H), −0.03 (s, 9H), 0.72 (t, 2H, J=8.0 Hz), 0.89 (t, 2H, J=8 Hz), 1.05 (s, 6H), 1.21-1.24 (m, 3H), 1.52-1.57 (m, 2H), 2.50 (s, 2H), 2.56-2.64 (m, 2H), 3.10-3.13 (m, 2H), 3.32-3.36 (m, 2H), 3.61 (t, 2H, J=8.0 Hz), 5.39 (s, 2H), 5.96 (s, 2H), 6.50 (s, 2H), 6.51-6.54 (m, 1H), 6.61 (brs, 1H), 7.27 (d, 1H, J=8.0 Hz).

Production of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-ethylacetamide

##STR00068##

In the same manner as in Example 1, Step 8, the title compound (24 mg, yield 35%) was obtained from N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylamine (110 mg, 0.19 mmol).

Example 3

Production of benzyl N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylcarbamate

##STR00069##

A solution of benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate (13 g, 19 mmol) obtained in Example 1, Step 6, in N,N-dimethylformamide (102 ml) was added to tetrabutylammonium fluoride (93 ml, 93 mmol) concentrated in advance under reduced pressure, and then ethylenediamine (19 ml) was added. The mixture was stirred with heating at 90° C. for 7 hr. After cooling, water and ethyl acetate were added, and the organic layer was separated. Then, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (7.2 g, yield 91%).

Example 4

Production of (S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamide

Production of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylamine

##STR00070##

Under a nitrogen atmosphere, to a solution of benzyl N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylcarbamate obtained in Example 3 (7.2 g, 17 mmol) in ethanol (72 ml) were added 10% palladium-carbon (723 mg) and ammonium formate (2.5 g, 39 mmol), and the mixture was stirred with heating at 65° C. for 40 min. After cooling, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was slurry-washed in water (300 ml). The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (4.5 g, yield 90%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.00 (s, 6H), 1.56 (t, 2H, J=6.41 Hz), 2.38 (s, 2H), 2.61 (t, 2H, J=6.41 Hz), 2.69 (d, 3H, J=4.81 Hz), 5.24-5.34 (m, 1H), 6.33-6.46 (m, 3H), 7.18 (d, 1H, J=8.41 Hz), 10.65 (s, 1H), 12.28 (s, 1H).

Production of (S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamide

##STR00071##

To a solution of N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylamine (45 mg, 0.15 mmol) in pyridine (1 ml) were added (S)-2-(morpholin-4-yl)propionic acid obtained in Reference Example 3 (110 mg, 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.55 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture were added chloroform and water, and the organic layer was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, the residue was dissolved in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml). To the solution was added 2 N aqueous sodium hydroxide solution (0.35 ml) at room temperature, and the mixture was stirred for 20 min. To the reaction mixture were added chloroform and water, and the organic layer was separated. The organic layer was dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (52 mg, yield 78%).

Example 5

Production of (S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamide hydrochloride

##STR00072##

To a solution of (S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamide obtained in Example 4 (100 mg, 0.23 mmol) in ethyl acetate (1 ml) was added 4 N hydrochloric acid/ethyl acetate (0.06 ml, 0.24 mmol) at room temperature, and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (75 mg, 69%).

Example 6

Production of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(3-oxomorpholin-4-yl)acetamide

##STR00073##

Under an argon atmosphere, to a solution of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylamine obtained in Example 4, Step 1 (40 mg, 0.14 mmol) and (3-oxomorpholin-4-yl)acetic acid obtained in Reference Example 4 (76 mg, 0.48 mmol) in pyridine (1.3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (91 mg, 0.48 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.2 ml), 2 N aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was stirred at room temperature for 45 min. Then, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (40 mg, yield 67%).

Example 7

Production of 2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl)methylamide

Production of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl)amide

##STR00074##

To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid obtained in Example 1, Step 4 (500 mg, 0.88 mmol) in N,N-dimethylformamide (5 ml) were added 1-hydroxybenzotriazole monohydrate (161 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.1 mmol) and 2-amino-1-propanol (84 mg, 1.1 mmol) at room temperature, and the mixture was stirred at room temperature for 7 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (511 mg, yield 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.22 (s, 9H), −0.03 (s, 9H), 0.68 (t, 2H, J=8.12 Hz), 0.87 (t, 2H, J=8.12 Hz), 1.03 (s, 6H), 1.17 (d, 3H, J=6.72 Hz), 1.54 (t, 2H, J=6.26 Hz), 2.50 (s, 2H), 2.62 (t, 2H, J=6.26 Hz), 3.29 (t, 2H, J=8.12 Hz), 3.35-3.39 (m, 1H), 3.48-3.53 (m, 1H), 3.60 (t, 2H, J=8.12 Hz), 4.01-4.11 (m, 1H), 4.74 (t, 1H, J=5.68 Hz), 5.41 (s, 2H), 6.11 (s, 2H), 6.76 (s, 1H), 7.57-7.67 (m, 2H), 8.01 (d, 1H, J=7.88 Hz), 8.15 (s, 1H).

Production of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid [2-(tert-butyldiphenylsilyloxy)-1-methylethyl]amide

##STR00075##

To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl)amide (265 mg, 0.42 mmol) in N,N-dimethylformamide (2.7 ml) were added imidazole (35 mg, 0.51 mmol) and tert-butyldiphenylsilyl chloride (132 μl, 0.51 mmol) under ice-cooling, and the mixture was stirred at room temperature for 8 hr. Then, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (341 mg, yield 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.24 (s, 9H), −0.03 (s, 9H), 0.64 (t, 2H, J=8.12 Hz), 0.87 (t, 2H, J=8.12 Hz), 1.00 (s, 9H), 1.02 (s, 6H), 1.26 (d, 3H, J=6.96 Hz), 1.53 (t, 2H, J=6.38 Hz), 2.50 (s, 2H), 2.60-2.65 (m, 2H), 3.24-3.28 (m, 5H), 3.55-3.65 (m, 3H), 3.70-3.77 (m, 1H), 4.23-4.34 (m, 1H), 5.41 (s, 2H), 6.09 (s, 2H), 6.76 (s, 1H), 7.36-7.47 (m, 6H), 7.58-7.67 (m, 6H), 8.10-8.16 (m, 2H).

##STR00076##

Under an argon atmosphere, to a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid [2-(tert-butyldiphenylsilyloxy)-1-methylethyl]amide (337 mg, 0.39 mmol) in N,N-dimethylformamide (3.4 ml) were added sodium hydride (19 mg, 0.47 mmol) and methyl iodide (36 μl, 0.58 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (149 mg, yield 44%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.23 (s, 9H), −0.05 (s, 9H), 0.59-0.62 (br m, 2H), 0.86 (dd, 2H, J=10.44, 5.80 Hz), 0.98 (s, 9H), 1.02 (s, 6H), 1.08 (br s, 3H), 1.54 (t, 2H, J=6.26 Hz), 2.50 (s, 2H), 2.61-2.64 (br m, 2H), 2.83 (s, 3H), 3.21-3.29 (m, 2H), 3.38-3.46 (m, 0.6H), 3.54-3.83 (m, 1.4H), 3.58 (t, 2H, J=8.00 Hz), 4.04-4.17 (m, 0.6H), 4.72-4.90 (br m, 0.4H), 5.39-5.41 (br m, 2H), 5.69-5.83 (m, 0.6H), 5.96-6.09 (m, 1.4H), 6.77 (s, 1H), 7.11 (d, 1H, J=9.04 Hz), 7.17-7.75 (m, 12H).

Production of 2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indole-6-carboxylic acid (2-hydroxy-1-methylethyl)methylamide

##STR00077##

A solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid [2-(tert-butyldiphenylsilyloxy)-1-methylethyl]methylamide (145 mg, 0.17 mmol) in N,N-dimethylformamide (1.2 ml) was added to tetrabutylammonium fluoride (1.7 ml, 1.7 mmol) concentrated in advance under reduced pressure. Ethylenediamine (0.29 ml) was added, and the mixture was stirred with heating at 90° C. for 14 hr. After cooling, to the mixture were added water and ethyl acetate, and the organic layer was separated, washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (57 mg, yield 90%).

Example 8

Production of N-[2-(6-hydroxymethyl-6-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(2-oxopiperidin-1-yl)acetamide

Production of N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine

##STR00078##

In the same manner as in Example 1, step 7, the title compound was obtained from tert-butyl 6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate obtained in Reference Example 5 and 1-tert-butyl 6-methyl 2-boronylindole-1,6-dicarboxylate obtained in Reference Example 2.

Production of N-(2-{6-hydroxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide

##STR00079##

To a solution of N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (150 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) were added (2-oxopiperidin-1-yl)acetic acid obtained in Reference Example 6 (43 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.27% mmol) and 1-hydroxybenzotriazole monohydrate (37 mg, 0.27 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg). Under a nitrogen atmosphere, to a solution of the obtained N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg) in a mixed solvent of methanol (0.8 ml) and tetrahydrofuran (0.8 ml) was added 20% palladium hydroxide-carbon (150 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at normal pressure for 4 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, yield 75%).

¹H-NMR (400 MHz, DMSO-d₆) δ: −0.21 (9H, s), −0.04 (9H, s), 0.67 (2H, t, J=7.86 Hz), 0.86 (2H, t, J=8.06 Hz), 0.93 (3H, s), 1.44-1.73 (6H, m), 2.12-2.21 (2H, m), 2.39 (1H, d, J=16.52 Hz), 2.59-2.65 (2H, m), 2.59 (1H, d, J=16.52 Hz), 3.22 (3H, s), 3.27 (2H, s), 3.31 (2H, t, J=8.06 Hz), 3.59 (2H, t, J=7.86 Hz), 3.81 (2H, s), 4.71 (1H, t, J=5.44 Hz), 5.38 (1H, d, J=11.28 Hz), 5.41 (1H, d, J=11.69 Hz), 6.02 (1H, d, J=10.48 Hz), 6.07 (1H, d, J=10.88 Hz), 6.74 (1H, s), 7.06 (1H, d, J=7.66 Hz), 7.60 (1H, s), 7.64 (1H, d, J=8.06 Hz).